Telaglenastat/Cabozantinib Does Not Significantly Improve PFS in Metastatic RCC, But Future Directions Hold Promise

Nizar Tannir, MD, FACP

Despite being well tolerated, the combination of telaglenastat (CB-839) plus cabozantinib (Cabometyx) did not demonstrate a significant improvement in progression-free survival (PFS) over cabozantinib alone in patients with metastatic renal cell carcinoma (mRCC), according to Nizar Tannir, MD, FACP. However, examining telaglenastat in biomarker-selected populations with a high dependence on glutamine/glutaminase and evaluating the agent in combination with other therapeutic partners may produce more positive results, according to Tannir.

Results from the phase 2 CANTATA trial (NCT03428217), which were presented during the 2021 ASCO Annual Meeting, showed that the combination yielded a median of 9.2 months (95% CI, 7.6-11.1) vs 9.3 months (95% CI, 7.6-11.0) with cabozantinib alone (hazard ratio [HR], 0.94; 95% CI, 0.74-1.21; P = .653) in this patient population (n = 444). Moreover, the overall response rate (ORR) was 31.2% with the combination vs 27.8% with cabozantinib alone, which was also not determined to be statistically significant.

“One should not be discouraged by a negative trial. So many agents have very strong [preclinical] rationale, they show encouraging results in phase 1 [trials], and then in large, randomized phase 3 trials, they end up being negative,” Tannir said. “It shows that we still have a long way to go [in terms of selecting] the proper patient population [for this regimen, and maybe, bringing back the concept of a biomarker-driven trial.”

In an interview with OncLive^®, Tannir, a professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, and Ransom Horne, Jr. Professorship for Cancer Research, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed the results of the phase 2 CANTATA trial with telaglenastat plus cabozantinib and future research directions for the glutaminase inhibitor.

OncLive^®: Could you speak to the rationale for evaluating telaglenastat in the CANTATA trial?

Tannir: [Many research efforts] have focused on targeted therapy. For example, in kidney cancer, [we know that] angiogenesis is important. [We also know the] importance of immune checkpoint inhibitors in many tumor types. [However,] tumor metabolism has emerged as an important area of research.

If we look at normal cells, [they] produce energy through glucose conversion, through the glycolysis mechanism, and by producing adenosine triphosphate [ATP] in the tricarboxylic acid cycle [TCA] cycle. Tumor cells, on the other hand, must rely on [a pathway] other than the glucose pathway for their metabolism, because there is conversion of glucose to lactate through the Warburg effect; that is where glutamine comes [in].

Telaglenastat is a glutaminase inhibitor that blocks the conversion of glutamine to glutaminase. Many tumor types rely on glutamine and glutaminase to produce their energy. This is the rationale for producing this agent.

Additionally, phase 1 trial [NCT02071862] combined telaglenastat with cabozantinib in a small number of heavily pretreated patients. We observed an ORR of 50% and a disease control rate of 100% with the regimen. This provided a good foundation to conduct this large, phase 3 trial.

What was the design of the study, and the key objectives of the research?

[CANTATA] is a large global, randomized, placebo-controlled, double-blind phase 3 trial. [Investigators] looked at combining an agent that is FDA approved in the salvage setting, the VEGF TKI cabozantinib, [with telaglenastat]. It is a rational combination based on data from preclinical studies, [which] showed the combination of everolimus [Afinitor] plus telaglenastat, [as well as] the combination of cabozantinib plus telaglenastat, had synergy in both in vitro [and] in vivo models. That is the scientific rationale for this combination.

The design [of the trial] was simple; [we evaluated] telaglenastat plus cabozantinib vs placebo plus cabozantinib in the second- and third-line treatment setting. Patients had to have received [prior treatment with] either nivolumab [Opdivo] plus ipilimumab [Yervoy] or antiangiogenic inhibitors, and up to 2 prior lines of therapy. Participants were randomized [in a] 1:1 [fashion]. The primary end point of the study was PFS. The trial was powered to answer the question of whether the combination of telaglenastat plus cabozantinib could produce an improvement in PFS, as assessed by an independent radiology committee [IRC]. A [total] of 444 patients were accrued to the trial.

[Additionally,] there were some assumptions [to note], which first started with the control arm. We know that in the phase 3 METEOR trial [NCT01865747], which compared single-agent cabozantinib with everolimus in the second- and third-line setting and beyond, [results showed a] median PFS of 7.4 months. As such, there were assumptions made for this trial to design it and calculate the sample size. We used 8 months as the median PFS for the control arm, and the HR was set at 0.69; that is how we came up with 444 [as our target number of patients to accrue to the trial].

What were the results that read out during the 2021 ASCO Annual Meeting?

Unfortunately, results did not show an improvement in PFS with the combination of telaglenastat plus cabozantinib compared with placebo plus cabozantinib. The median PFS by IRC assessment in both arms proved to be very similar, at 9.2 months and 9.3. months, [respectively]; this shows that there is really no advantage or [PFS] benefit [derived from] the [experimental] combination. The data regarding responses to treatment were consistent [with this finding]; the ORR was 31% in the experimental arm vs 28% in the placebo arm, so no real difference between the arms.

[In terms of] overall survival [OS], most patients were still alive at the time of the analysis, or at the time of data cutoff, which was August 31, 2020. [Approximately] 35% of the patients had died on the experimental arm vs [approximately] 31% on the placebo arm. [The OS data are still] considered to be immature. In the future, we will have longer follow-up data from the study to assess OS. However, in terms of the primary end point of PFS, no difference [was observed] between the 2 arms.

What did the safety profile of the combination look like?

Data from a prior phase 1 trial [NCT02071862] that examined telaglenastat alone in heavily pretreated patients demonstrated a very tolerable profile, with very few adverse effects [AEs] reported; these effects were mostly grade 1 or 2. [Common AEs included] nausea, fatigue, photophobia, a slight elevation in liver function tests, diarrhea, and rash, [which are] typical [toxicities that we see with] targeted agents. Overall, the agent was well tolerated, and had a low discontinuation rate.

In terms of the AEs in CANTATA, they were very comparable between the arms. Any-grade AEs [were reported in about 99% of patients] in both arms, [and they] were consistent with either agent when it is given alone. The notable grade 3 AEs were diarrhea and hypertension; these were driven mostly by cabozantinib. [In terms of the] discontinuation rate, 10% of patients discontinued therapy in the experimental arm vs 15% in the placebo arm, and [approximately 80% of patients] required a dose interruption or reduction of cabozantinib on both arms.

What are your thoughts on why the trial turned out to be negative?

This [trial] obviously [had] an unselected patient population; it [was] not based on biomarkers. Why did the telaglenastat plus cabozantinib combination not show superiority in terms of PFS compared with placebo plus cabozantinib? Was the partner, cabozantinib, not the correct partner? If we go back to the hypothesis, which is tumor metabolism, is blocking the glutamine pathway relevant in oncology? I do believe it is. There is a high expression of this enzyme in many tumor types, and there are strong preclinical data in vitro and in vivo to suggest that this is a relevant pathway in oncology and tumor metabolism. [However,] could another agent combined with telaglenastat show a positive result?

[Data from a previous phase 2] study, [ENTRATA; NCT03163667], were presented during the 2019 ESMO Congress. Here, everolimus was combined with telaglenastat and compared with placebo plus everolimus. [This was a] smaller study of 69 patients; it had a similar design, [but] a 2:1 randomization. In that study, the PFS was also the primary end point, and the medium PFS was doubled with telaglenastat plus everolimus in a very heavily pretreated patient population, at 3.8 months vs 1.9 months with placebo plus everolimus. [As such, in terms of] blocking glucose and glutamine, these 2 pathways are important in tumor metabolism; [these data proved that] the hypothesis was correct. However, maybe the CANTATA study was negative because cabozantinib may not have been the best partner for [telaglenastat].

Where should future efforts be focused with telaglenastat?

Thinking forward, [we could evaluate the regimen in] a more selected patient population with tumors that are more metabolically driven rather than unselected [patients with] clear cell RCC. It is important to mention that there is a phase 2 study [NCT04265534] combining telaglenastat with chemotherapy in patients with nonsquamous non–small cell lung cancer that are driven by a mutation. Therefore, maybe in that patient population that is biomarker selected, we will see positive results. [Additionally,] some other ideas are being formulated to see whether we can test the same combination in other rare tumors of the kidney.

Reference

1. Tannir N, Agarwal N, Porta C, et al. CANTATA: Primary analysis of a global, randomized, placebo (Pbo)-controlled, double-blind trial of telaglenastat (CB-839) + cabozantinib versus Pbo + cabozantinib in advanced/metastatic renal cell carcinoma (mRCC) patients (pts) who progressed on immune checkpoint inhibitor (ICI) or anti-angiogenic therapies. J Clin Oncol. 2021;39(supp 15):4501. doi:10.1200/JCO.2021.39.15_suppl.4501